Solid state forms of relugolix

ABSTRACT

The present disclosure provides solid state forms of Relugolix, crystalline forms of Relugolix, pharmaceutical compositions thereof, and pharmaceutical formulations thereof. Methods for producing these forms of Relugolix, pharmaceutical compositions, and pharmaceutical formulations are also provided.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation in part of U.S. patent applicationSer. No. 16/980,507 filed Sep. 14, 2020, which is a National Stage of,and claims priority to and the benefit of, International PatentApplication No. PCT/US2019/022169 filed Mar. 14, 2019, which, in turn,claims the benefit of, and priority to, U.S. Provisional PatentApplication No. 62/642,649, filed Mar. 14, 2018 and U.S. ProvisionalPatent Application No. 62/661,752, filed Apr. 24, 2018, the entiredisclosures of each of which are incorporated by reference herein.

FIELD OF THE DISCLOSURE

The present disclosure encompasses solid state forms of Relugolix, inembodiments crystalline polymorphs of Relugolix, processes forpreparation thereof, and pharmaceutical compositions thereof.

BACKGROUND OF THE DISCLOSURE

Relugolix's chemical name is1-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxypyridazin-3-yl)-2,4-dioxo-1,2,3,4-tetrahydrothieno(2,3-d)pyrimidin-6-yl)phenyl)-3-methoxyurea,having the following chemical structure:

Relugolix is a selective antagonist of Gonadotropin-Releasing HormoneReceptor, under development for the treatment of certain pathologies,e.g., endometriosis, uterine leiomyoma, and prostate cancer.

The compound is described in PCT publication WO 2004/067535. PCTpublication WO 2010/026993 relates to pharmaceutical compositionscontaining, inter alia, Relugolix. WO 2014/051164 relates to processesand crystalline forms of Relugolix. WO 2016/136849 relates to a solidpreparation, e.g., tablet, containing Relugolix. In addition, J. Med.Chem., 2011, 54 (14), pp. 4998-5012, refers, inter alia, topharmacological and chemical aspects of this molecule.

Polymorphism, the occurrence of different crystalline forms, is aproperty of some molecules and molecular complexes. A single moleculemay give rise to a variety of polymorphs having distinct crystalstructures and physical properties, like melting point, thermalbehaviors (e.g., measured by thermogravimetric analysis—“TGA,” ordifferential scanning calorimetry—“DSC”), X-ray diffraction (XRD)pattern, infrared absorption fingerprint, and solid state (¹³C) NMRspectrum. One or more of these techniques may be used to distinguishdifferent polymorphic forms of a compound.

Different salts and solid state forms (including solvated forms) of anactive pharmaceutical ingredient may possess different properties. Suchvariations in the properties of different salts and solid state formsand solvates may provide a basis for improving formulation, for example,by facilitating better processing or handling characteristics, changingthe dissolution profile in a favorable direction, or improving stability(polymorph as well as chemical stability) and shelf-life. Thesevariations in the properties of different salts and solid state formsmay also offer improvements to the final dosage form, for instance, ifthey serve to improve bioavailability. Different salts and solid stateforms and solvates of an active pharmaceutical ingredient may also giverise to a variety of polymorphs or crystalline forms, which may in turnprovide additional opportunities to assess variations in the propertiesand characteristics of a solid active pharmaceutical ingredient.

Discovering new solid state forms and solvates of a pharmaceuticalproduct may yield materials having desirable processing properties, suchas ease of handling, ease of processing, storage stability, and ease ofpurification or as desirable intermediate crystal forms that facilitateconversion to other polymorphic forms. New solid state forms of apharmaceutically useful compound can also provide an opportunity toimprove the performance characteristics of a pharmaceutical product. Itenlarges the repertoire of materials that a formulation scientist hasavailable for formulation optimization, for example, by providing aproduct with different properties, e.g., a different crystal habit,higher crystallinity, or polymorphic stability, which may offer betterprocessing or handling characteristics, improved dissolution profile, orimproved shelf-life (chemical/physical stability). For at least thesereasons, there is a need for additional solid state forms (includingsolvated forms) of Relugolix.

SUMMARY OF THE DISCLOSURE

The present disclosure provides crystalline polymorphs of Relugolix,processes for preparation thereof, and pharmaceutical compositionsthereof. These crystalline polymorphs can be used to prepare other solidstate forms of Relugolix, Relugolix salts and their solid state forms.

The present disclosure provides crystalline polymorphs of Relugolix foruse in the preparation of pharmaceutical compositions and/orformulations for use in medicine, in embodiments for the treatment ofendometriosis, uterine leiomyoma, and/or prostate cancer.

The present disclosure also encompasses the use of crystallinepolymorphs of Relugolix of the present disclosure for the preparation ofpharmaceutical compositions and/or formulations.

A method of the present disclosure may include dissolving Relugolix FormF in a first solvent to form a solution, contacting the solution with asecond solvent to form a suspension, cooling the suspension, andrecovering Relugolix Form B.

In embodiments, the first solvent is dimethyl sulfoxide.

In some embodiments, dissolving Relugolix Form F in the first solventoccurs at a temperature from about 30° C. to about 50° C. In otherembodiments dissolving Relugolix Form F in the first solvent occurs at atemperature from about 35° C. to about 45° C.

In embodiments, the second solvent is ethanol.

In some embodiments, contacting the solution with the second solvent toform the suspension occurs at a temperature from about 30° C. to about50° C. In other embodiments, contacting the solution with the secondsolvent to form the suspension occurs at a temperature from about 35° C.to about 45° C.

In embodiments, contacting the solution with the second solvent to formthe suspension occurs for a period of time from about 30 minutes toabout 90 minutes. In some embodiments, contacting the solution with thesecond solvent to form the suspension occurs for a period of time fromabout 45 minutes to about 75 minutes.

In other embodiments, contacting the solution with the second solvent toform the suspension occurs with stirring.

In embodiments, cooling the suspension cools the suspension to atemperature from about 15° C. to about 50° C. In other embodiments,cooling the suspension cools the suspension to a temperature from about20° C. to about 45° C.

In some embodiments, cooling the suspension occurs for a period of timefrom about 30 minutes to about 90 minutes. In other embodiments, coolingthe suspension occurs for a period of time from about 45 minutes toabout 75 minutes.

In embodiments, the method further includes stirring the suspension fora period of time from about 8 hours to about 20 hours after cooling thesuspension.

In some embodiments, recovering the Relugolix Form B occurs byfiltration. In other embodiments, the filtration is vacuum filtration.

The crystalline polymorph of Relugolix as defined herein and thepharmaceutical compositions or formulations of the crystalline polymorphof Relugolix may be used as medicaments, in embodiments for thetreatment of endometriosis, uterine leiomyoma, and/or prostate cancer.

The present disclosure also provides methods of treating endometriosis,uterine leiomyoma, and/or prostate cancer, by administering atherapeutically effective amount of a crystalline polymorph of Relugolixof the present disclosure, or at least one of the above pharmaceuticalcompositions or formulations, to a subject suffering from endometriosis,uterine leiomyoma, prostate cancer, or otherwise in need of thetreatment.

The present disclosure also provides the uses of crystalline polymorphsof Relugolix of the present disclosure, or at least one of the abovepharmaceutical compositions or formulations, for the manufacture ofmedicaments for treating e.g., endometriosis, uterine leiomyoma and/orprostate cancer.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows a characteristic X-ray powder diffraction pattern (XRPD) ofRelugolix Form F (as hemihydrate).

FIG. 2 shows a characteristic X-ray powder diffraction pattern (XRPD) ofRelugolix Form G.

FIG. 3 shows a characteristic X-ray powder diffraction pattern (XRPD) ofRelugolix Form H.

FIG. 4 shows a characteristic X-ray powder diffraction pattern (XRPD) ofpolymorphically pure Relugolix Form G.

FIG. 5 shows a characteristic X-ray powder diffraction pattern (XRPD) ofamorphous Relugolix.

FIG. 6a shows a characteristic FT-IR spectrum of Relugolix Form F (fullrange).

FIG. 6b shows a characteristic FT-IR spectrum of Relugolix Form F(zoomed-in).

FIG. 7 shows a characteristic X-ray powder diffraction pattern (XRPD) ofRelugolix Form F (anhydrous).

FIG. 8 shows a calculated XRPD pattern of Relugolix Form J (determinedfrom crystal data obtained at 180 K).

DETAILED DESCRIPTION OF THE DISCLOSURE

The present disclosure encompasses solid state forms of Relugolix, suchas crystalline polymorphs of Relugolix, processes for preparationthereof, and pharmaceutical compositions thereof.

Solid state properties of Relugolix and crystalline polymorphs thereofcan be influenced by controlling the conditions under which Relugolixand crystalline polymorphs thereof are obtained in solid form.

A solid state form (or polymorph) may be referred to herein aspolymorphically pure or as substantially free of any other solid state(or polymorphic) forms. As used herein in this context, the expression“substantially free of any other forms” will be understood to mean thatthe solid state form contains about 20% (w/w) or less, about 10% (w/w)or less, about 5% (w/w) or less, about 2% (w/w) or less, about 1% (w/w)or less, or about 0% of any other forms of the subject compound asmeasured, for example, by XRPD. Thus, a crystalline polymorph ofRelugolix described herein as substantially free of any other solidstate forms would be understood to contain greater than about 80% (w/w),greater than about 90% (w/w), greater than about 95% (w/w), greater thanabout 98% (w/w), greater than about 99% (w/w), or about 100% of thesubject crystalline polymorph of Relugolix. In some embodiments of thedisclosure, the described crystalline polymorph of Relugolix may containfrom about 1% to about 20% (w/w), from about 5% to about 20% (w/w), orfrom about 5% to about 10% (w/w) of one or more other crystallinepolymorph of the same Relugolix.

Depending on any other crystalline polymorphs with which a comparison ismade, the crystalline polymorphs of Relugolix of the present disclosurehave advantageous properties selected from at least one of thefollowing: chemical purity, flowability, solubility, dissolution rate,morphology or crystal habit, stability—such as chemical stability aswell as thermal and mechanical stability with respect to polymorphicconversion, stability towards dehydration and/or storage stability, lowcontent of residual solvent, a lower degree of hygroscopicity,flowability, and advantageous processing and handling characteristicssuch as compressibility, and bulk density.

A solid state form, such as a crystal form or an amorphous form, may bereferred to herein as being characterized by graphical data “as depictedin” or “as substantially depicted in” a Figure. Such data include, forexample, powder X-ray diffractograms and solid state NMR spectra. As iswell-known in the art, the graphical data potentially providesadditional technical information to further define the respective solidstate form (a so-called “fingerprint”) which cannot necessarily bedescribed by reference to numerical values or peak positions alone. Inany event, the skilled person will understand that such graphicalrepresentations of data may be subject to small variations, e.g., inpeak relative intensities and peak positions due to certain factors suchas, but not limited to, variations in instrument response and variationsin sample concentration and purity, which are well known to the skilledperson. Nonetheless, the skilled person would readily be capable ofcomparing the graphical data in the Figures herein with graphical datagenerated for an unknown crystal form and confirm whether the two setsof graphical data are characterizing the same crystal form or twodifferent crystal forms. A crystal form of Relugolix referred to hereinas being characterized by graphical data “as depicted in” or “assubstantially depicted in” a Figure will thus be understood to includeany crystal forms of Relugolix characterized with the graphical datahaving such small variations, as are well known to the skilled person,in comparison with the Figure.

As used herein, and unless stated otherwise, the term “anhydrous” inrelation to crystalline forms of Relugolix, relates to a crystallineform of Relugolix which does not include any crystalline water (or othersolvents) in a defined, stoichiometric amount within the crystal.Moreover, an “anhydrous” form would typically not contain more than 1%(w/w), of either water or organic solvents as measured, for example, byTGA.

The term “solvate,” as used herein and unless indicated otherwise,refers to a crystal form that incorporates a solvent in the crystalstructure. When the solvent is water, the solvate is often referred toas a “hydrate.” The solvent in a solvate may be present in either astoichiometric or in a non-stoichiometric amount.

As used herein, and unless indicated otherwise, the term “wetcrystalline form” refers to a polymorph that was not dried using anyconventional techniques to remove residual solvent. Examples of suchconventional techniques can be, but are not limited to, evaporation,vacuum drying, oven drying, drying under nitrogen flow, etc.

As used herein, and unless indicated otherwise, the term “drycrystalline form” refers to a polymorph that was dried using anyconventional techniques to remove residual solvent. Examples of suchconventional techniques can be, but are not limited to, evaporation,vacuum drying, oven drying, drying under nitrogen flow, etc.

As used herein, the term “isolated” in reference to a crystallinepolymorph of Relugolix of the present disclosure corresponds to acrystalline polymorph of Relugolix that is physically separated from thereaction mixture in which it is formed.

As used herein, unless stated otherwise, the XRPD measurements are takenusing copper Kα radiation wavelength 1.54187 Å (1.5419 Å). XRPD peaksreported herein are measured using CuK α radiation, λ=1.54187 Å (1.5419Å), typically at a temperature of 25±3° C.

A thing, e.g., a reaction mixture, may be characterized herein as beingat, or allowed to come to “room temperature” or “ambient temperature,”often abbreviated as “RT.” This means that the temperature of the thingis close to, or the same as, that of the space, e.g., the room or fumehood, in which the thing is located. Typically, room temperature is fromabout 20° C. to about 30° C., or about 22° C. to about 27° C., or about25° C.

The amount of solvent employed in a chemical process, e.g., a reactionor crystallization, may be referred to herein as a number of “volumes”or “vol” or “V.” For example, a material may be referred to as beingsuspended in 10 volumes (or 10 vol or 10V) of a solvent. In thiscontext, this expression would be understood to mean milliliters of thesolvent per gram of the material being suspended, such that suspending a5 grams of a material in 10 volumes of a solvent means that the solventis used in an amount of 10 milliliters of the solvent per gram of thematerial that is being suspended or, in this example, 50 mL of thesolvent. In another context, the term “v/v” may be used to indicate thenumber of volumes of a solvent that are added to a liquid mixture basedon the volume of that mixture. For example, adding solvent X (1.5 v/v)to a 100 ml reaction mixture would indicate that 150 mL of solvent X wasadded.

A process or step may be referred to herein as being carried out“overnight.” This refers to a time interval, e.g., for the process orstep, that spans the time during the night, when that process or stepmay not be actively observed. This time interval is from about 8 toabout 20 hours, or about 10-18 hours, in embodiments about 16 hours.

As used herein, the term “reduced pressure” refers to a pressure that isless than atmospheric pressure. For example, reduced pressure is about10 mbar to about 50 mbar.

As used herein and unless indicated otherwise, the term “ambientconditions” refer to atmospheric pressure and a temperature of 22-24° C.

As used herein, the term “crystalline '816” refers to the crystallineform described in US 2018/0319816 (counterpart of WO 2014/051164), FIG.2 and/or table 2 therein.

The present disclosure includes a crystalline polymorph of Relugolix,designated Form F. The crystalline Form F of Relugolix may becharacterized by data selected from one or more of the following: anX-ray powder diffraction pattern substantially as depicted in FIG. 1 orin FIG. 7; an X-ray powder diffraction pattern having peaks at 6.9, 7.5,9.5, 13.9 and 18.1 degrees 2-theta±0.2 degrees 2-theta; an FT-IRspectrum having peaks at 1720, 1680, 1626, 1595, 1528, 1460, 1412, 1313,1237 and 1095 cm⁻¹±4 cm⁻¹; an FT-IR spectrum substantially as depictedin FIGS. 6a and/or 6 b; and combinations of these data.

Crystalline Form F of Relugolix may be further characterized by dataselected from one or more of the following: an X-ray powder diffractionpattern having peaks at 6.9, 7.5, 9.5, 13.9 and 18.1 degrees 2-theta±0.2degrees 2-theta, and also having any one, two, three, four or fiveadditional peaks selected from the group consisting of 10.2, 12.9, 19.1,21.1 and 23.2 degrees 2-theta±0.2 degrees 2-theta; an FT-IR spectrumhaving peaks at 3477, 3298, 3223, 3069, 2991, 2952, 2862, 2827, 2782,1720, 1680, 1626, 1595, 1528, 1460, 1412, 1384, 1350, 1313, 1237, 1212,1180, 1149, 1113, 1095, 1032, 1014, 973, 936, 836, 808, 784, 769, 746,727, 684, 647, 628 and 598 cm⁻¹±4 cm⁻¹; and combinations of these data.

In embodiments, crystalline Form F of Relugolix may have a melting pointof about 204° C. as measured by DSC, and/or of about 198° C. as measuredby capillary method.

In embodiments, crystalline Form F of Relugolix is an iso-structuralpolymorph, i.e., it may be either anhydrous, a hydrate, preferably ahemi-hydrate, or a solvate.

Crystalline Form F of Relugolix may be characterized by each of theabove characteristics alone or by all possible combinations, e.g., anXRPD pattern having peaks at 6.9, 7.5, 9.5, 13.9 and 18.1 degrees2-theta±0.2 degrees 2-theta; an XRPD pattern as depicted in FIG. 1; anXRPD pattern as depicted in FIG. 1 and melting point of about 198° C. asmeasured by capillary method; and combinations thereof.

In one embodiment of the present disclosure, crystalline Form F ofRelugolix is isolated.

Depending on any other crystalline polymorphs with which a comparison ismade, crystalline Form F of Relugolix of the present disclosure hasadvantageous properties as described above. For example, crystallineForm F possesses advantageous solubility behavior at physiological pHvalues, such as 4.8 and/or 6.8, which are highly relevant for APIabsorption from oral dosage form.

The present disclosure further provides Form F substantially free ofother solid state forms of Relugolix. In embodiments the Form F includes20% or less, 15% or less, 10% or less, 5% or less, 2% or less or 1% orless of other solid state forms of Relugolix as determined by XPRD. Insome embodiments the Form F includes 0.5% or less, 0.25% or less, 0.1%or less, or undetectable amounts of other solid state forms of Relugolixas determined by XRPD.

The present disclosure further includes a crystalline polymorph ofRelugolix, designated Form G. The crystalline Form G of Relugolix may becharacterized by data selected from one or more of the following: anX-ray powder diffraction pattern substantially as depicted in FIG. 2; anX-ray powder diffraction pattern having peaks at 5.4, 8.4, 10.7 and 12.1degrees 2-theta±0.2 degrees 2-theta; and combinations of these data.

Crystalline Form G of Relugolix may be further characterized by an X-raypowder diffraction pattern having peaks at 5.4, 8.4, 10.7 and 12.1degrees 2-theta±0.2 degrees 2-theta, and also having any one, two, threeor four additional peaks selected from the group consisting of 6.9, 7.7,17.4 and 19.2 degrees 2-theta±0.2 degrees 2-theta.

Crystalline Form G of Relugolix may be characterized by each of theabove characteristics alone or by all possible combinations, e.g., anXRPD pattern having peaks at 5.4, 8.4, 10.7 and 12.1 degrees 2-theta±0.2degrees 2-theta; an XRPD pattern as depicted in FIG. 2, and combinationsthereof.

In one embodiment of the present disclosure, crystalline Form G ofRelugolix is isolated.

In embodiments, the present disclosure relates to a polymorphically pureForm G of Relugolix; i.e., crystalline Relugolix Form G that issubstantially free of any other forms, as described herein above. Inembodiments, it is substantially free of crystalline Relugolix Form H.Accordingly, the content of crystalline Relugolix Form H in crystallineRelugolix Form G is measured by detecting and quantifying the describedcharacteristic peaks of Form H. The characteristic peaks of crystallineRelugolix Form H used for the above described measurement can beselected from the peaks at about 8.4 and/or 19.2 degrees two theta±0.2degrees two theta.

The above polymorphically pure Form G of Relugolix may be characterizedby data selected from one or more of the following: an X-ray powderdiffraction pattern substantially as depicted in FIG. 4; an X-ray powderdiffraction pattern having peaks at 3.4, 5.6, 9.6, 13.3 and 17.4 degrees2-theta±0.2 degrees 2-theta; and combinations of these data.Polymorphically pure Form G of Relugolix may be further characterized byan X-ray powder diffraction pattern having peaks at 3.4, 5.6, 9.6, 13.3and 17.4 degrees 2-theta±0.2 degrees 2-theta, and also having any one,two, three, four or five additional peaks selected from 7.7, 11.7, 12.2,23.5 and 25.7 degrees 2-theta±0.2 degrees 2-theta.

Polymorphically pure Form G of Relugolix may be characterized by each ofthe above characteristics alone/or by all possible combinations, e.g.,an XRPD pattern having peaks at 3.4, 5.6, 9.6, 13.3 and 17.4 degrees2-theta±0.2 degrees 2-theta; an XRPD pattern as depicted in FIG. 4, andcombinations thereof.

The present disclosure further includes a crystalline polymorph ofRelugolix, designated Form H. The crystalline Form H of Relugolix may becharacterized by data selected from one or more of the following: anX-ray powder diffraction pattern substantially as depicted in FIG. 3; anX-ray powder diffraction pattern having peaks at 6.2, 8.6, 15.9, 19.0and 19.6 degrees 2-theta±0.2 degrees 2-theta; and combinations of thesedata.

Crystalline Form H of Relugolix may be further characterized by an X-raypowder diffraction pattern having peaks at 6.2, 8.6, 15.9, 19.0 and 19.6degrees 2-theta±0.2 degrees 2-theta, and also having any one, two, threeor four additional peaks selected from 10.1, 11.5, 12.3 and 22.0 degrees2-theta±0.2 degrees 2-theta.

Crystalline Form H of Relugolix may be characterized by each of theabove characteristics alone or by all possible combinations, e.g., anXRPD pattern having peaks at 6.2, 8.6, 15.9, 19.0 and 19.6 degrees2-theta±0.2 degrees 2-theta; an XRPD pattern as depicted in FIG. 3, andcombinations thereof.

In one embodiment of the present disclosure, crystalline Form H ofRelugolix is isolated.

The present disclosure further includes a crystalline polymorph ofRelugolix, designated Form J. The crystalline Form J of Relugolix may becharacterized as a having triclinic crystal system, having space groupof P1 and having unit cell dimensions of about a=14.3 Å±0.5 Å, b=15.0Å±0.5 Å, c=16.5 Å±0.5 Å and unit cell volume of about V=3082 Å³±10 Å³when determined at 180 K.

Crystalline Form J of Relugolix may be further characterized by acalculated X-ray powder diffraction pattern as depicted in FIG. 8.

In one embodiment of the present disclosure, crystalline Form J ofRelugolix is isolated.

Crystalline Form J of Relugolix may be a solvated, hydrated crystallineform. In embodiments crystalline Form J of Relugolix prepared accordingto Example 8 corresponds to hemi acetonitrile solvate, hemihydrate (theunit cell contains four molecules of Relugolix, two molecules ofacetonitrile and two molecules of water).

Form J as described in any embodiment disclosed herein may be used toprepare Form F as described in any embodiment disclosed herein. Inembodiments, the Form F is prepared from Form J by drying or partialdrying (i.e., solvent removal or partial solvent removal), e.g., at atemperature of 30-80° C., for a sufficient time to prepare Form F asdescribed in any embodiment herein (in embodiments 2-8 hours, in someembodiments 3-6, hours or about 4 to about 5 hours)

The present invention also describes amorphous Relugolix. The amorphousis typically characterized by an X-ray powder diffraction patternsubstantially as depicted in FIG. 5.

The step of isolating Relugolix or a crystalline polymorph of Relugolixmay be performed by crystallization.

The above crystalline polymorphs can be used to prepare othercrystalline polymorphs of Relugolix, Relugolix salts and their solidstate forms.

For example, in embodiments Crystalline Form F of Relugolix may be usedto form other forms of Relugolix, including Crystalline Form B ofRelugolix. As used herein, “Crystalline Form B of Relugolix” or“Relugolix Form B” may be used interchangeably, and mean1-{4-[1-(2,6-difluorobenzyl)-5-dimethylaminomethyl-3-(6-methoxypyridazin-3-yl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl]phenyl}-3-methoxyurea),a form of Relugolix disclosed in Example 8 and FIG. 2 of U.S. Pat. No.10,464,945.

A process for producing Relugolix Form B from Relugolix Form F inaccordance with the present disclosure may include the following.Relugolix Form F may first be dissolved in a suitable solvent, sometimesreferred to herein as a first solvent, at a suitable temperature to forma solution. Suitable solvents for use as the first solvent include, forexample, dimethyl sulfoxide (DMSO). The Relugolix Form F in solution maybe at a temperature from about 30° C. to about 50° C., in embodimentsfrom about 35° C. to about 45° C., in some embodiments about 35° C.

An additional solvent, sometimes referred to herein as a second solvent,may then be gradually added to the solution and, after signs of crystalformation, stirred at a suitable temperature for a suitable period oftime to form a suspension. Suitable solvents that may be used as thesecond solvent include, for example, ethanol (EtOH). The addition of thesecond solvent may occur with stirring at a temperature from about 30°C. to about 50° C., in embodiments from about 35° C. to about 45° C., insome embodiments about 35° C., for a period of time from about 30minutes to about 90 minutes, in embodiments from about 45 minutes toabout 75 minutes, in embodiments for about 60 minutes.

The suspension may then be cooled to a temperature from about 15° C. toabout 50° C., in embodiments from about 20° C. to about 45° C., in someembodiments about 25° C., over a period of time from about 30 minutes toabout 90 minutes, in embodiments from about 45 minutes to about 75minutes, in embodiments for about 60 minutes. The suspension may then bestirred at this cooled temperature for a suitable period of time, inembodiment from about 8 hours to about 20 hours, in embodiments fromabout 11 hours to about 17 hours, in embodiments about 14 hours. Thesuspension may then be subjected to filtration, in embodiments vacuumfiltration, with the obtained crystals dried on the filter under vacuumfor a suitable period of time, in embodiments about 30 minutes.

The present disclosure provides crystalline polymorphs of Relugolix foruse in the preparation of pharmaceutical compositions includingRelugolix and/or crystalline polymorphs thereof.

The present disclosure also encompasses the use of crystallinepolymorphs of Relugolix of the present disclosure for the preparation ofpharmaceutical compositions of crystalline polymorph Relugolix and/orcrystalline polymorphs thereof.

The present disclosure includes processes for preparing the abovementioned pharmaceutical compositions. The processes include combiningthe crystalline polymorphs of Relugolix of the present disclosure withat least one pharmaceutically acceptable excipient.

Pharmaceutical formulations of the present invention contain any one ora combination of the solid state forms of Relugolix of the presentdisclosure, in embodiments crystalline Relugolix Form F. In addition tothe active ingredient, the pharmaceutical formulations of the presentdisclosure can contain one or more excipients. Excipients are added tothe formulation for a variety of purposes.

Diluents increase the bulk of a solid pharmaceutical composition, andcan make a pharmaceutical dosage form containing the composition easierfor the patient and caregiver to handle. Diluents for solid compositionsinclude, for example, microcrystalline cellulose (e.g. Avicel®),microfine cellulose, lactose, starch, pregelatinized starch, calciumcarbonate, calcium sulfate, sugar, dextrates, dextrin, dextrose, dibasiccalcium phosphate dihydrate, tribasic calcium phosphate, kaolin,magnesium carbonate, magnesium oxide, maltodextrin, mannitol,polymethacrylates (e.g. Eudragit®), potassium chloride, powderedcellulose, sodium chloride, sorbitol, and talc.

Solid pharmaceutical compositions that are compacted into a dosage form,such as a tablet, can include excipients whose functions include helpingto bind the active ingredient and other excipients together aftercompression. Binders for solid pharmaceutical compositions includeacacia, alginic acid, carbomer (e.g. carbopol), carboxymethylcellulosesodium, dextrin, ethyl cellulose, gelatin, guar gum, hydrogenatedvegetable oil, hydroxyethyl cellulose, hydroxypropyl cellulose (e.g.Klucel®), hydroxypropyl methyl cellulose (e.g. Methocel®), liquidglucose, magnesium aluminum silicate, maltodextrin, methylcellulose,polymethacrylates, povidone (e.g. Kollidon®, Plasdone®), pregelatinizedstarch, sodium alginate, and starch.

The dissolution rate of a compacted solid pharmaceutical composition inthe patient's stomach can be increased by the addition of a disintegrantto the composition. Disintegrants include alginic acid,carboxymethylcellulose calcium, carboxymethylcellulose sodium (e.g.Ac-Di-Sol®, Primellose®), colloidal silicon dioxide, croscarmellosesodium, crospovidone (e.g. Kollidon®, Polyplasdone®), guar gum,magnesium aluminum silicate, methyl cellulose, microcrystallinecellulose, polacrilin potassium, powdered cellulose, pregelatinizedstarch, sodium alginate, sodium starch glycolate (e.g. Explotab®), andstarch.

Glidants can be added to improve the flowability of a non-compactedsolid composition and to improve the accuracy of dosing. Excipients thatcan function as glidants include colloidal silicon dioxide, magnesiumtrisilicate, powdered cellulose, starch, talc, and tribasic calciumphosphate.

When a dosage form such as a tablet is made by the compaction of apowdered composition, the composition is subjected to pressure from apunch and dye. Some excipients and active ingredients have a tendency toadhere to the surfaces of the punch and dye, which can cause the productto have pitting and other surface irregularities. A lubricant can beadded to the composition to reduce adhesion and ease the release of theproduct from the dye. Lubricants include magnesium stearate, calciumstearate, glyceryl monostearate, glyceryl palmitostearate, hydrogenatedcastor oil, hydrogenated vegetable oil, mineral oil, polyethyleneglycol, sodium benzoate, sodium lauryl sulfate, sodium stearyl fumarate,stearic acid, talc, and zinc stearate.

Flavoring agents and flavor enhancers make the dosage form morepalatable to the patient. Common flavoring agents and flavor enhancersfor pharmaceutical products that can be included in the composition ofthe present invention include maltol, vanillin, ethyl vanillin, menthol,citric acid, fumaric acid, ethyl maltol, and tartaric acid.

Solid and liquid compositions can also be dyed using anypharmaceutically acceptable colorant to improve their appearance and/orfacilitate patient identification of the product and unit dosage level.

In liquid pharmaceutical compositions of the present disclosure,Relugolix and any other solid excipients are dissolved or suspended in aliquid carrier such as water, vegetable oil, alcohol, polyethyleneglycol, propylene glycol, or glycerin.

Liquid pharmaceutical compositions can contain emulsifying agents todisperse uniformly throughout the composition an active ingredient orother excipient that is not soluble in the liquid carrier. Emulsifyingagents that can be useful in liquid compositions of the presentdisclosure include, for example, gelatin, egg yolk, casein, cholesterol,acacia, tragacanth, chondrus, pectin, methyl cellulose, carbomer,cetostearyl alcohol, and cetyl alcohol.

Liquid pharmaceutical compositions of the present disclosure can alsocontain a viscosity enhancing agent to improve the mouth-feel of theproduct and/or coat the lining of the gastrointestinal tract. Suchagents include acacia, alginic acid bentonite, carbomer,carboxymethylcellulose calcium or sodium, cetostearyl alcohol, methylcellulose, ethylcellulose, gelatin guar gum, hydroxyethyl cellulose,hydroxypropyl cellulose, hydroxypropyl methyl cellulose, maltodextrin,polyvinyl alcohol, povidone, propylene carbonate, propylene glycolalginate, sodium alginate, sodium starch glycolate, starch tragacanth,and xanthan gum.

Sweetening agents such as sorbitol, saccharin, sodium saccharin,sucrose, aspartame, fructose, mannitol, and invert sugar can be added toimprove the taste.

Preservatives and chelating agents such as alcohol, sodium benzoate,butylated hydroxyl toluene, butylated hydroxyanisole, andethylenediamine tetraacetic acid can be added at levels safe foringestion to improve storage stability.

According to the present disclosure, a liquid composition can alsocontain a buffer such as gluconic acid, lactic acid, citric acid, oracetic acid, sodium gluconate, sodium lactate, sodium citrate, or sodiumacetate. Selection of excipients and the amounts used can be readilydetermined by the formulation scientist based upon experience andconsideration of standard procedures and reference works in the field.

The solid compositions of the present disclosure include powders,granulates, aggregates, and compacted compositions. The dosages includedosages suitable for oral, buccal, rectal, parenteral (includingsubcutaneous, intramuscular, and intravenous), inhalant, and ophthalmicadministration. Although the most suitable administration in any givencase will depend on the nature and severity of the condition beingtreated, in embodiments the route of administration is oral. The dosagescan be conveniently presented in unit dosage form and prepared by anymethod well-known in the pharmaceutical arts.

Dosage forms include solid dosage forms like tablets, powders, capsules,suppositories, sachets, troches, and lozenges, as well as liquid syrups,suspensions, and elixirs.

The dosage form of the present disclosure can be a capsule containingthe composition, in embodiments a powdered or granulated solidcomposition of the disclosure, within either a hard or soft shell. Theshell can be made from gelatin and optionally contain a plasticizer suchas glycerin and sorbitol, and an opacifying agent or colorant.

The active ingredient and excipients can be formulated into compositionsand dosage forms according to methods known in the art.

A composition for tableting or capsule filling can be prepared by wetgranulation. In wet granulation, some or all of the active ingredientsand excipients in powder form are blended and then further mixed in thepresence of a liquid, typically water, that causes the powders to clumpinto granules. The granulate is screened and/or milled, dried, and thenscreened and/or milled to the desired particle size. The granulate canthen be tableted, or other excipients can be added prior to tableting,such as a glidant and/or a lubricant.

A tableting composition can be prepared conventionally by dry blending.For example, the blended composition of the actives and excipients canbe compacted into a slug or a sheet and then comminuted into compactedgranules. The compacted granules can subsequently be compressed into atablet.

As an alternative to dry granulation, a blended composition can becompressed directly into a compacted dosage form using directcompression techniques. Direct compression produces a more uniformtablet without granules. Excipients that are particularly well suitedfor direct compression tableting include microcrystalline cellulose,spray dried lactose, dicalcium phosphate dihydrate, and colloidalsilica. The proper use of these and other excipients in directcompression tableting is known to those in the art with experience andskill in particular formulation challenges of direct compressiontableting.

A capsule filling of the present disclosure can include any of theaforementioned blends and granulates that were described with referenceto tableting, but they are not subjected to a final tableting step.

A pharmaceutical formulation of Relugolix can be administered. Relugolixmay be formulated for administration to a mammal, in embodiments ahuman, by injection. Relugolix can be formulated, for example, as aviscous liquid solution or suspension, in embodiments a clear solution,for injection. The formulation can contain one or more solvents. Asuitable solvent can be selected by considering the solvent's physicaland chemical stability at various pH levels, viscosity (which wouldallow for syringeability), fluidity, boiling point, miscibility, andpurity. Suitable solvents include alcohol USP, benzyl alcohol NF, benzylbenzoate USP, and Castor oil USP. Additional substances can be added tothe formulation such as buffers, solubilizers, and antioxidants, amongothers. Ansel et al., Pharmaceutical Dosage Forms and Drug DeliverySystems, 7th ed.

The crystalline polymorphs of Relugolix and the pharmaceuticalcompositions and/or formulations of Relugolix of the present disclosurecan be used as medicaments, in embodiments for the treatment ofendometriosis, uterine leiomyoma, and/or prostate cancer.

The present disclosure also provides methods of treating endometriosis,uterine leiomyoma, and/or prostate cancer by administering atherapeutically effective amount of a crystalline polymorph of Relugolixof the present disclosure, or at least one of the above pharmaceuticalcompositions and/or formulations, to a subject in need of the treatment.

Having thus described the disclosure with reference to particularpreferred embodiments and illustrative examples, those in the art canappreciate modifications to the disclosure as described and illustratedthat do not depart from the spirit and scope of the disclosure asdisclosed in the specification. The Examples are set forth to aid inunderstanding the disclosure but are not intended to, and should not beconstrued to limit its scope in any way.

XRPD Method

Powder X-ray Diffraction was performed on an X-Ray powder diffractometerPanAlytical X'pert Pro; CuKα radiation λ=1.54187 (1.5419 Å); X'Celeratordetector with active length 2.122 degrees 2-theta; laboratorytemperature 25±3° C.; zero background sample holders. Prior to analysis,the samples were gently ground using a mortar and pestle to obtain afine powder. The ground sample was adjusted into a cavity of the sampleholder and the surface of the sample was smoothed using a cover glass.

Measurement Parameters:

Scan range 3-40 degrees 2-theta Scan mode continuous Step size 0.0167degrees Step size 42 s Sample spin 60 rpm Sample holder zero backgroundsilicon plate

FT-IR Method

KBr pellet was prepared and FTIR transmission spectrum was recorded onNicolet 380 spectrometer, equipped with KBr beam splitter and DTGS KBrdetector.

Instrument Parameters:

Spectral range: 4000-550 cm⁻¹ Resolution: 4.0 cm⁻¹ Number of scans: 64Sample gain: 1 Optical velocity: 0.6329 Aperture: 100

Melting-Point Capillary Measurement

Melting point was measured by capillary method according to USP <741>:

Equipment: Capillary automated melting point analyzer MPA100 OptiMelt;Heating range: 35-205° C.; Heating rate: 1.0° C./min; Evaluation: Anarithmetic mean of the clear point values in three parallel capillarieswas adopted as a melting point result.

X-Ray Crystal Structure Determination

Data were collected on a Rigaku Xcalibur PX system equipped with OnyxCCD detector and a Cu Kα sealed tube (λ=1.5418 Å) with an Enhancedmonochromator using combined φ and ω scans at 180 K. Data collection:CrysAlisPro CCD (Oxford Diffraction, 2002); cell refinement: CrysAlisProRED; data reduction: CrysAlisPro RED; program used to solve structure:Sir92 (Altomare et al., 1994); and void calculation was done by Platon(Spek, 2003).

Oxford Diffraction (2002). CrysAlisPro. Version 171.31.7 OxfordDiffraction Ltd, 68 Milton Park, Abingdon, Oxfordshire OX14 4RX,England.

SIR92—Altomare, A., Cascarano, G., Giacovazzo, G., Guagliardi, A.,Burla, M. C., Polidori, G., Camalli, M. (1994). J. Appl. Cryst. 27, 435.

PLATON ver. 191114—Spek, A. L. (2003). PLATON, A MultipurposeCrystallographic Tool, Utrecht University, Utrecht, The Netherlands.

DSC Measurement Parameters

Equipment: TA Discovery; Crucibles: Aluminum Tzero pans with pin-holedTzero hermetic lids, 40 μl; Heating range: 25-300° C.; Heating rate: 10°C./min Purging gas: Nitrogen; Purging gas flow: 50 ml/min

Preparation of Starting Materials

Relugolix can be prepared according to methods known from the literature(for example, see WO 2004/067535; WO 2014/051164; and J. Med. Chem.,2011, 54 (14), pp. 4998-5012).

Example 1. Preparation of Relugolix Form F

Relugolix (470 mg) was fully dissolved at Di-methyl-sulphoxide (DMSO, 2ml) at room temperature and a solution was obtained. The solution washeated to a temperature of 35° C., and 18 ml of Ethyl-acetate wereadded; then, the solution was cooled down to 5° C. over a period of 30minutes and was stirred for additional 30 minutes and a clear solutionwas obtained. At this stage, 50 ml of water was added to the clearsolution. After the addition of water, the solution became cloudy andwas stirred for 60 minutes, and placed in a refrigerator. After 5 daysthe crystals were collected by filtration, and dried on the filter for30 minutes. The material was further dried at 50° C. for 5 hours underNitrogen (N₂) stream.

Yield: 200 mg; dry material.

A sample was analyzed by XRPD; Form F was obtained. XRPD pattern isdepicted in FIG. 1. The obtained product was hemihydrate form.

Example 2. Preparation of Relugolix Form G

Relugolix (50 mg) was suspended in dichloromethane (1 ml), the obtainedsuspension was heated up to temperature 38° C. during 120 minutes. Aclear solution was obtained at around 22-23° C. The solution was thenstirred at temperature 38° C. for 30 minutes; subsequently, the clearsolution was cooled down during 120 minutes from 38° C. to thetemperature (−5)° C. and stirred at this temperature for 30 minutes.Filtration was performed and the obtained wet crystals were left for 30minutes, on the filter under Nitrogen (N₂) stream.

Yield: around 20 mg of white wet solid.

A sample was analyzed by XRPD, Form G was obtained. XRPD pattern isdepicted in FIG. 2.

Example 3. Preparation of Relugolix Form H

Relugolix (500 mg) was suspended in dichloromethane (10 ml). Theobtained suspension was heated up to temperature 38° C. during 90minutes. A clear solution was obtained at around 22-23° C. The solutionwas then stirred at temperature 38° C. for 30 minutes; subsequently, theclear solution was cooled down during 90 minutes from 38° C. to thetemperature (−5)° C. and stirred at this temperature for 30 minutes.Filtration was performed, and the obtained wet crystals were left for 30minutes on the filter under Nitrogen (N₂) stream. The obtained materialwas dried on air for 16 hours at room temperature. Yield: 200 mg.

A sample was analyzed by XRPD, Form H was obtained. XRPD pattern isdepicted in FIG. 3.

Example 4. Preparation of Relugolix Form G—Polymorphically Pure

Relugolix (3000 mg) was suspended in dichloromethane (60 ml). Theobtained suspension was heated up to temperature of 32° C. over a periodof 30 minutes. A clear solution was obtained at around 22-23° C. and wasfiltrated through a folded filter. The solution was then stirred attemperature of 20° C. for 5 minutes; subsequently, the clear solutionwas cooled down over a period of 60 minutes from 20° C. to thetemperature (−5)° C. and was stirred at this temperature for 3.5 hours.Then, filtration was performed, the mother liquor was reserved for thesubsequent procedure and the obtained wet crystals were left for 30minutes on the filter under Nitrogen (N₂) stream. A sample was analyzedby XRPD, polymorphically pure Form G was obtained. XRPD pattern isdepicted in FIG. 4.

Example 5. Preparation of Amorphous Relugolix

The dichloromethane mother liquor isolated in Example 4 (50 ml) wasevaporated into dryness using a rotary vacuum evaporator. The conditionsof evaporation: temperature of the bath 40° C., vacuum 25 mbar. Time ofevaporation 30 minutes.

Yield from evaporation: 2.2 grams of the amorphous substance.

A sample was analyzed by)(RFD, amorphous was obtained. XRPD pattern isdepicted in FIG. 5.

Example 6. Preparation of Relugolix Form F

Relugolix (50 mg, amorphous) was suspended in water and the obtainedsuspension was heated up to temperature of 95° C. over a period of about2 hours. The suspension was then stirred at temperature of 95° C. for aperiod of about 30 minutes and then the suspension was cooled down totemperature of (−5)° C. over a period of about 2 hours and was furtherstirred at temperature of (−5)° C. for a period of about 30 minutes. Thesuspension was filtered and the obtained wet crystals were left for 15minutes on the filter under Nitrogen (N₂) stream. Yield: 45 mg of whitewet solid. A sample was analyzed by XRPD, Form F was obtained; theobtained product was hemihydrate.

Example 7. Preparation of Relugolix Form F (Hemihydrate)

Relugolix (5 grams) was suspended in acetonitrile (300 ml) and theobtained suspension was heated up to temperature of 78° C. over a periodof about 30 minutes. A clear solution was obtained. Subsequently, theclear solution was cooled down over a period of about 1 hour fromtemperature of about 78° C. to temperature of about 20° C. and water(500 ml) was added over a period of about 60 minutes. The solution wasstirred at this temperature for 30 minutes and then cooled down totemperature of about 2° C. over a period of about 60 minutes, and acloudy solution was formed. The cloudy solution was then stirred attemperature of about 2° C. for 12 hours, then it was filtered andobtained wet crystals were left for 30 minutes on the filter underNitrogen (N₂) stream. The crystals were then dried under stream ofNitrogen (N₂) at temperature of about 70° C. for 5 hours. A sample wasanalyzed by XRPD, Form F was obtained; the obtained product was ahemihydrate.

Example 8. Preparation of Relugolix Form F (Anhydrous)

The product obtained in Example 7 was further heated by a TGA apparatusto temperature of about 140° C. (heating rate 10° C./min). A sample wasanalyzed by XRPD, Form F was maintained; XRPD pattern is depicted inFIG. 7. The obtained product was anhydrous.

Example 9. Preparation of Relugolix Form J

Relugolix (100 mg) was dissolved in acetonitrile (8 ml). Water (6 ml)was added with stirring at ambient temperature, and the open vial wasplaced into a box at 4° C. overnight. Then, the volume of solution wasreduced to about ⅔ on a vacuum evaporator and the reduced solution wasplaced again into a box at 4° C., overnight. Colorless crystals wereformed and a sample was covered by paraffin oil after removal frommother's liquor. A sample was analyzed by Single X-ray crystallographicanalysis (180K), Form J was obtained; the obtained product was a hemiacetonitrile solvate, hemihydrate. Calculated XRPD pattern is presentedin FIG. 8.

Example 10. Preparation of Relugolix Form F

Relugolix (80 mg) was dissolved in THF (8.5 ml) and then water (8.5 ml)was added. The solution was put into a cooler at 4° C. for a period ofabout 12 hours. Then, the sample was divided into two equal parts. Tothe part A, additional volume of water (5 ml) was added. The volume ofpart B was reduced to about ½ on a vacuum evaporator. Both samples wereplaced again into the cooler at 4° C. for a period of about 12 hours,and crystals were formed. The mother liquor was poured out and removedand both samples were dried at 40° C. and 500 Pa for a period of 10minutes. A sample was analyzed by XRFD, Form F was obtained, as ahemihydrate.

Example 11. Preparation of Relugolix Form F

Relugolix (80 mg) was dissolved in acetone (7.5 ml) and water (7.5 ml)was added. The solution was put into a cooler at 4° C. for a period ofabout 12 hours. Then, about ½ of solution was evaporated on vacuumevaporator and sample was placed again into the cooler at 4° C. for aperiod of about 12 hours and crystals were formed. The mother liquor waspoured out and removed and sample was dried at 40° C. and 500 Pa for aperiod of 10 minutes. A sample was analyzed by XRFD, Form F wasobtained.

Example 12. Preparation of Relugolix Form B

Relugolix Form F (300 mg) was dissolved in DMSO (1.1 ml) at 35° C.Ethanol (6.6 ml) was gradually added and in a few minutescrystallization started. The suspension was stirred at 35° C. for 1hour. The suspension was then cooled down to 25° C. over a period of 1hour and the suspension was stirred at this temperature for 14 hours.The suspension was then subjected to filtration, with obtained crystalsdried on filter under vacuum for 30 minutes. Yield: 210 mg of RelugolixForm B.

1. A method comprising: dissolving Relugolix Form F in a first solventto form a solution; contacting the solution with a second solvent toform a suspension; cooling the suspension; and recovering Relugolix FormB.
 2. The method of claim 1, wherein the first solvent is dimethylsulfoxide.
 3. The method of claim 1, wherein dissolving Relugolix Form Fin the first solvent occurs at a temperature from about 30° C. to about50° C.
 4. The method of claim 1, wherein dissolving Relugolix Form F inthe first solvent occurs at a temperature from about 35° C. to about 45°C.
 5. The method of claim 1, wherein the second solvent is ethanol. 6.The method of claim 1, wherein contacting the solution with the secondsolvent to form the suspension occurs at a temperature from about 30° C.to about 50° C.
 7. The method of claim 1, wherein contacting thesolution with the second solvent to form the suspension occurs at atemperature from about 35° C. to about 45° C.
 8. The method of claim 1,wherein contacting the solution with the second solvent to form thesuspension occurs for a period of time from about 30 minutes to about 90minutes.
 9. The method of claim 1, wherein contacting the solution withthe second solvent to form the suspension occurs for a period of timefrom about 45 minutes to about 75 minutes.
 10. The method of claim 1,wherein contacting the solution with the second solvent to form thesuspension occurs with stirring.
 11. The method of claim 1, whereincooling the suspension cools the suspension to a temperature from about15° C. to about 50° C.
 12. The method of claim 1, wherein cooling thesuspension cools the suspension to a temperature from about 20° C. toabout 45° C.
 13. The method of claim 1, wherein cooling the suspensionoccurs for a period of time from about 30 minutes to about 90 minutes.14. The method of claim 1, wherein cooling the suspension occurs for aperiod of time from about 45 minutes to about 75 minutes.
 15. The methodof claim 1, further comprising stirring the suspension for a period oftime from about 8 hours to about 20 hours after cooling the suspension.16. The method of claim 1, wherein recovering the Relugolix Form Boccurs by filtration.
 17. The method of claim 16, wherein the filtrationis vacuum filtration.